CN102850347A - Resolution method for pyrazole derivative or salt thereof - Google Patents
Resolution method for pyrazole derivative or salt thereof Download PDFInfo
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Abstract
The invention discloses a resolution method for a pyrazole derivative or a salt thereof. The method comprises the following steps: reacting a raceme compound as represented by formula 1 or a salt thereof with a resolving reagent in a resolving solvent at a temperature of -10 to 50 DEG C to produce a diastereomer chiral acid salt and allowing the diastereomer chiral acid salt to be precipitated from the resolving solvent at a temperature of -10 to 50 DEG C; placing the diastereomer chiral acid salt in a crystallization solvent for one crystallization or multiple times of recrystallization; and subjecting the chiral acid salt as represented by formula 2 or formula 3 and an alkali to a neutralization reaction to dissociate a compound as represented by formula 2 or formula 3. The method provided by the invention has the following advantages: a process is stable; quality is controllable; raw and accessory materials are easily available; the method is simple to operate; the compound as represented by formula 1 is used as a raw material for resolution, which enables cost to be low; and a single chiral compound obtained after resolution has optical purity as high as 99.9%, meeting medicinal standard.
Description
Technical field
The invention belongs to racemize and split the field, be specifically related to a kind of racemic modification compound 3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8, the method for splitting of 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone or its salt.
Background technology
Single configuration of compound 3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (formula 2 or formula 3) is the key intermediate of the disclosed PARP inhibitor medicaments of patent WO2007095628A1.
Wherein M for without or but be not limited to mineral acid, example hydrochloric acid, hydrogen bromide, carbonic acid; And organic acid, such as Phenylsulfonic acid, acetic acid, formic acid.
PARP is one of most important novel targets of recent in the world antineoplastic new medicine research and development, and U.S.'s " prevention " magazine was chosen as one of 9 quantum jumps of world's field of medicaments most worthy in 2009 with the most obstinate cancer of PARP inhibitor antagonism in 2009.
Poly-adenosine diphosphate (ADP) ribose polymerase (poly (ADP-ribose) polymerase, PARP), being also referred to as poly-adenosine diphosphate (ADP) ribose synthetic enzyme (PARS) or poly-adenosine diphosphate (ADP) transferring enzyme (PADPRT), is to be present in one of key cells ribozyme family in the eukaryotic cell.In people's systemic cell especially in immunocyte and sexual cell the content of PARP quite enrich.In a lot of physiological processs the generation of poly-ADP ribose is arranged, its multiple action comprises the copying of chromatinic degraded, DNA, the reparation of DNA, the expression of gene, the division of cell and the apoptosis of differentiation and cell.PARP during by excessive activation, will consume a large amount of NAD in the dna damage process, and then will exhaust the ATP in the cell, be that cell is in the energy deficiency state, thereby cause necrosis or the apoptosis of cell.
The research of PARP inhibitor worldwide, has been subject to making earnest efforts of various countries' scientists at present.The main pharmacy group in the world all begins to drop into the PARP inhibitor of a large amount of research and development strength development oneself, comprises that at present the PARP inhibitor of six esbablished corporation research and development such as Merck, AstraZeneca, Abbott Laboratories has all entered the clinical study stage.
Patent WO2007095628A1 discloses compound (S/R)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8, the preparation method of 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (formula 2 or formula 3 compounds) (as shown in the formula):
This patent adopts the method for chiral chromatographic column preparation to carry out compound from formula 4 compounds and splits, and then deprotection obtains formula 2 or formula 3 compounds.The method has that the experiment yield is low, and synthetic cost is high, and the production cycle is long, should not realize the shortcoming such as industrialization.
The contriver has carried out multiple means and has carried out the fractionation research of formula 1 compound.The compound that at first prepares the single chiral configuration from synthetic angle: adopt single chiral compound (formula 5) as raw material, wish by synthetic method, obtain (S/R)-3-methyl isophthalic acid of single configuration-(pyrazole-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (formula 2 or formula 3).But result of study shows, employing formula 5 compounds are as raw material, synthetic method according to the compound of the similar structures of mentioning among the patent WO2007095628A1, namely take n-Butyl Lithium as alkali, under-78 ℃, react, product also is easy to occur racemization, thus, can not obtain the target compound (formula 2 or formula 3) of single chiral configuration.Even if the change reaction conditions can access target compound (formula 2 or formula 3), but the compound of single chiral configuration is higher as the starting raw material price, and the polystep reaction overall yield is lower, further increase synthetic cost.In addition, the contriver has also carried out the fractionation research of chiral column chromatogram, although successfully separate, finds that its cost is also relatively high, should not realize industrialization.
Summary of the invention
The objective of the invention is in order to overcome defective of the prior art, a kind of racemic modification compound 3-methyl isophthalic acid-(pyrazole-3-yl)-6 are provided, 7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (suc as formula 1 compound) or its salt, by splitting preparation single chiral compound (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (suc as formula 2 compounds) or its salt, or (R)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7, the method of 8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (suc as formula 3 compounds) or its salt.
Purpose of the present invention can reach by following measures:
A kind of method for splitting of formula 1 compound or its salt, it comprises the steps:
(1) split: racemic modification formula 1 compound or its salt and resolution reagent in-10 ℃～50 ℃ reaction generation diastereomer chirality hydrochlorates, are separated out from resolution solvent under temperature-10 ℃～50 ℃ in resolution solvent again;
(2) recrystallization: diastereomer chirality hydrochlorate places recrystallisation solvent to carry out the one or many recrystallization, until diastereomer chirality hydrochlorate is purified to more than 99.9%;
(3) neutralization: the formula 2 that step (2) is obtained or chirality hydrochlorate and the alkali of formula 3 carry out neutralization reaction, dissociate formula 2 or formula 3 compounds, and obtain formula 2 or formula 3 compounds by the mode of filtration or solvent extraction.
The salt of racemic modification formula 1 compound is not limited to mineral acid, example hydrochloric acid, hydrogen bromide, carbonic acid; And organic acid, such as Phenylsulfonic acid, acetic acid, formic acid.
Resolution reagent of the present invention is selected from D-(+)-dibenzoyl tartaric acid or its hydrate; L-(-)-dibenzoyl tartaric acid or its hydrate; the D-dextrocamphoric acid; the L-dextrocamphoric acid; D-Arg; L-arginine; D-tartrate; L-TARTARIC ACID; D-ASP; ASPARTIC ACID; left-handed o-Chloromelic acid; the dextrorotation o-Chloromelic acid; D-(+)-to methyldiphenyl formyl tartrate or its hydrate; L-(-)-to methyldiphenyl formyl tartrate or its hydrate; D-(+)-diacetylation tartrate or its hydrate; D-(-)-diacetylation tartrate or its hydrate; D-(+)-di-p-methoxy benzoyl tartrate or its hydrate; D-(+)-di-p-methoxy benzoyl tartrate or its hydrate.
Preferred resolution reagent is D-(+)-dibenzoyl tartaric acid or its hydrate, L-(-)-dibenzoyl tartaric acid or its hydrate.
The present invention find number that whether above resolution reagent contain crystal water and contain crystal water on split result almost without impact.
Method of the present invention is jointly to place solvent to react salify formula 1 compound of racemic modification and resolution reagent, then separate out under certain conditions the little diastereoisomeric salt of solubleness, in solvent, carry out once again or repeatedly this salt of recrystallization purifying can obtain the diastereomer chirality hydrochlorate of the high single configuration of optical purity to objective optics purity.For the diastereomer compound of the single configuration that obtains dissociating, can adopt in the alkali and the diastereomer chirality hydrochlorate that reaches the single configuration of objective optics purity obtained above, the compound of the single configuration that dissociates.
In above-mentioned steps 1 splitting step, resolution reagent is 0.1～30:1 with the molar weight ratio of racemic modification formula 1 compound, is preferably 0.5～5:1, more preferably 1.05～2:1.
Resolution solvent of the present invention or recrystallisation solvent are independently selected from respectively water, methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, 1,2-ethylene dichloride, 1, one or more mixed solvents in the solvent of alcohols, ketone, haloalkane hydro carbons or other classifications such as 1-ethylene dichloride, chloroform, ethyl acetate, ether, benzene, toluene, tetrahydrofuran (THF), morpholine; Described resolution solvent preferably makes water, methylene dichloride and methanol mixed solvent; Described recrystallisation solvent preferably makes two or three mixed solvent in water, methylene dichloride and the methyl alcohol, and in recrystallization process, methylene dichloride can use together with other solvents or add in Crystallization Process and use.
Preferably, the consumption of resolution solvent is V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=0～200:0～200:0～200:1, the preferred solvent amount is V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=1～40:1～40:1～40:1.
During step 1 split, the temperature of reaction of racemic modification formula 1 compound or its salt and resolution reagent was-10 ℃～50 ℃, more preferably 5 ℃～30 ℃; The temperature of separating out diastereomer chirality hydrochlorate from resolution solvent is-10～50 ℃, is preferably 0～20 ℃, more preferably 10～15 ℃; Stirring or leave standstill the time of separating out is preferably 0.5h～72h, further preferred 10～15 hours.
Re-crystallization step in the step 2 is: after diastereomer chirality hydrochlorate places recrystallisation solvent, at-10 ℃～100 ℃ lower 0.1-20h that stir, then at-10 ℃～50 ℃ lower crystallization 0.5-72h, filter.In the crystallisation process, methylene dichloride can use together with other solvents or add in Crystallization Process and use.
In step 2 recrystallization, the stirring before the crystallization is preferably carried out under-10 ℃～100 ℃, further preferably carries out under 50 ℃～80 ℃; Churning time before the crystallization is preferably 0.5～2h; Tc is preferably 0 ℃～40 ℃, further preferred 0 ℃～5 ℃; Crystallization time is preferably 10～15h.
Preferably, the consumption of each solvent is V in step 2 recrystallization
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=0～200:0～200:0～200:1 is preferably V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=1～40:1～40:1～40:1.
If one time recrystallized product does not reach optical purity, can continue to improve optical purity with this step, can be purified to more than 99.9%.If recrystallization purifying repeatedly, the miss the mark optical purity, can be with after its salinization, free go on a tour from formula 1 compound, then extract with organic solvent, evaporate to dryness is removed formula 1 compound that obtains dissociating behind the solvent, and then prepares according to the method described above the higher diastereomer chirality hydrochlorate of optical purity with chiral acid.
Formula 2 in the step 3 or the chirality hydrochlorate of formula 3 are the purity that obtains in the step 2 at the diastereomer chirality hydrochlorate more than 99.9%.
In the step 3 and in, when the formula 2 that preparation is free or formula 3 compound, chirality hydrochlorate with the recrystallization preparation is added to the water, simultaneously at room temperature to wherein adding the alkali neutralization, (the pH value is to 7-14 to neutral or alkalescence to regulate pH, further be 7-8) after, filter cake diluted alkaline water washing filtered, then after washing with water, the single chiral compound that can obtain dissociating.
Alkali described in the present invention for but be not limited to the oxyhydroxide of metal, such as sodium hydroxide, potassium hydroxide; Metal carbonic acid thing is such as salt of wormwood, yellow soda ash; The hydrogen-carbonate thing of metal, as: sodium bicarbonate, saleratus, or the aqueous solution of above-mentioned alkali.
The present invention also comprises the method for splitting that splits mother liquor Chinese style 1 compound or its salt, and it comprises the steps:
(1) split: racemic modification formula 1 compound or its salt and resolution reagent in-10 ℃～50 ℃ reaction generation diastereomer chirality hydrochlorates, are separated out from resolution solvent under temperature-10 ℃～50 ℃ in resolution solvent again;
(2) reuse splits mother liquor: separate out in the splitting step fractionation mother liquor behind the diastereomer chirality hydrochlorate concentrated after, with alkali neutralization resolution reagent wherein, use again with step 1 in method in the resolution reagent repeating step 1 of opposite configuration separate out diastereomer chirality hydrochlorate;
(3) recrystallization: reuse is split the diastereomer chirality hydrochlorate that obtains in the mother liquor step place recrystallisation solvent to carry out the one or many recrystallization, until diastereomer chirality hydrochlorate is purified to more than 99.9%;
(4) formula 2 that re-crystallization step is obtained or the chirality hydrochlorate of formula 3 and alkali carry out neutralization reaction, and is free and filter out formula 2 or formula 3 compounds.Actual conditions in the method for splitting of this fractionation mother liquor in each step is with above-mentioned method for splitting.
Method for splitting of the present invention, it is the method that adopts chemistry to split, its characteristics are process stabilizing, quality controllable, supplementary material is easy to get, simple to operate, that final compound formula 1 take reaction scheme is as raw material simultaneously, split, with low cost, the single chiral compound optical purity that obtains after the fractionation is up to more than 99.9%, reach medicinal standard, to promoting the research of PARP inhibitor new drug, play very important effect.
Embodiment
To help to understand the present invention by the following example, but be not limited to content of the present invention.
Raceme among the embodiment or its salt, and in fractionation or the recrystallization purifying process, the e.e value of diastereomer chirality hydrochlorate is by high-performance liquid chromatogram determination, design parameter is as follows:
Chromatographic column: Chiralpak AD-H 250mm*4.6mm 5um
Moving phase: ethanol: (normal hexane-Virahol=95:5)=20:80(0.4%DEA)
Flow velocity: 1.000ml/min
Detector: UV305nm
Embodiment 1
With 400g racemic modification compound 3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; 8; 9-tetrahydrochysene-3H-pyrazolo [3; 4-c] isoquinoline 99.9-5(4H)-ketone (HPLC measures its content S:R=45.2%:54.8%); 700g D-(+)-dibenzoyl tartaric acid, 8L methyl alcohol, 4L methylene dichloride and 2L water join the 20L there-necked flask, 10 ~ 15 ℃ of lower mechanical stirring 12h crystallizations, suction filtration.60 ℃ of forced air dryings get 474g pale solid (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8, the D-(+) of 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt.
With above-mentioned 474g pale solid and according to V
Methyl alcohol/ ml:V
Water/ ml:M
Racemic modification chirality hydrochlorate/ g=5:1.25:1 ratio adds 2370mL methyl alcohol, 592.5mL water joins in the 10L there-necked flask, and oil bath is heated to little boiling (64 ℃ of interior temperature) under the mechanical stirring, behind the insulation 0.5h, with ice-water bath reaction solution is down to 20 ℃, slowly adds 1185mL(V
Methylene dichloride/ ml:M
Racemic modification chirality hydrochlorate/ g=2.5:1) methylene dichloride, 10-15 ℃ is stirred 15h crystallization, water pump suction filtration, 60 ℃ of forced air dryings.
Further crystallization is measured by HPLC: (S)-and 3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7,8,9-tetrahydrochysene-3H-pyrazolo [3; 4-c] isoquinoline 99.9-5(4H)-ketone D-(+)-the dibenzoyl tartaric acid salts contg is 99.92%; enantiomorph (R)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8; 9-tetrahydrochysene-3H-pyrazolo [3; 4-c] content of D-(+)-dibenzoyl tartaric acid salt of isoquinoline 99.9-5(4H)-ketone is 0.08%, gets the 337g white solid, yield 36.4%.
With 337 (the S)-3-methyl isophthalic acid that restrains-(pyrazole-3-yl)-6; 7; 8; 9-tetrahydrochysene-3H-pyrazolo [3; 4-c] D-(+)-dibenzoyl tartaric acid salt of isoquinoline 99.9-5(4H)-ketone joins in the water of 1.2L; at room temperature to the aqueous sodium hydroxide solution that wherein adds 40%, regulate about PH to 6 after, again to wherein adding sodium bicarbonate solid; after transferring pH to 7-8; the solid that filtration obtains is again with dilute aqueous solution of sodium bicarbonate washing 2 times, wash again 2 times with water after, filter; obtain 134.8 gram white solids after the drying; yield 33.7%, measure through HPLC: (S)-3-methyl isophthalic acid-(pyrazoles-3 base)-6,7; 8; 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone D-(+)-the dibenzoyl tartaric acid salts contg is 99.93%, enantiomorph (R)-3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; the content of the D-(+) of 8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt is 0.07%.
Embodiment 2
With 275g racemic modification compound 3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; 8; 9-tetrahydrochysene-3H-pyrazolo [3; 4-c] isoquinoline 99.9-5(4H)-ketone (HPLC measures its content S:R=43.1%:56.9%); 485g L-(-)-dibenzoyl tartaric acid; 5.5L methyl alcohol; 2.75L methylene dichloride and 1.375L water join the 20L there-necked flask; 10 ~ 15 ℃ of lower mechanical stirring 12h crystallizations; the water pump suction filtration, 60 ℃ of forced air dryings get 341g pale solid (R-3-methyl isophthalic acid-(pyrazoles-3 base)-6; 7; the D-(+) of 8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt.
With above-mentioned 341g pale solid and according to V
Methyl alcohol/ ml:V
Water/ ml:M
Racemic modification chirality hydrochlorate/ g=5:1.25:1 ratio adds 1705mL methyl alcohol, 426.3mL water joins in the 10L there-necked flask, and oil bath is heated to little boiling (64 ℃ of interior temperature) under the mechanical stirring, behind the insulation 0.5h, with ice-water bath reaction solution is down to 20 ℃, slowly adds 852.5mL(V
Dichloromethane Alkane/ ml:M
Racemic modification chirality hydrochlorate/ g=2.5:1) methylene dichloride, 10-15 ℃ is stirred 15h crystallization, water pump suction filtration, 60 ℃ of forced air dryings.
Dry product repeats above-mentioned crystallization purifying experimental technique.
Further HPLC measures after the crystallization: (R)-and 3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7,8,9-tetrahydrochysene-3H-pyrazolo [3; 4-c] isoquinoline 99.9-5(4H)-ketone D-(+)-the dibenzoyl tartaric acid salts contg is 99.90%; enantiomorph (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8; 9-tetrahydrochysene-3H-pyrazolo [3; 4-c] content of D-(+)-dibenzoyl tartaric acid salt of isoquinoline 99.9-5(4H)-ketone is 0.1%, gets the 236g white solid, yield 37.1%.
With 236 (the R)-3-methyl isophthalic acid that restrains-(pyrazole-3-yl)-6; 7; 8; the D-(+) of 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt joins in the water of 0.76L, at room temperature to the aqueous sodium hydroxide solution that wherein adds 40%; after regulating about pH to 6; to wherein adding sodium bicarbonate solid, behind the accent pH to 8, suction filtration goes out solid again.Solid washs 2 times with dilute aqueous solution of sodium bicarbonate; after washing 2 times with water; obtain 92.8 gram white solids after the forced air drying; yield is 33.7%; HPLC measures: (R)-and 3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; 8; 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone D-(+)-the dibenzoyl tartaric acid salts contg is 99.90%, enantiomorph (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; the content of the D-(+) of 8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt is 0.1%.
Embodiment 3
With 512 gram racemic modification compound 3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone (HPLC measures its content S:R=46.1%:53.9%) adopts the method for embodiment 1 to split to obtain (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6,7,8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] fractionation mother liquor and crystalline mother solution behind isoquinoline 99.9-5(4H)-ketone, carry out underpressure distillation after the merging, evaporate to dryness organic solvent wherein obtains turbid solution.Under stirring, in turbid solution, add about 40% aqueous sodium hydroxide solution adjusting pH to 6-7, in the aqueous solution, adding saturated aqueous solution of sodium bicarbonate, regulate about pH to 8, after stirring, suction filtration.
The solid that leaches, with 60 degrees centigrade of air blast oven dry after an amount of water washing, obtain 271 gram solids (HPLC measures its content S:R=17.6%:82.4%) and process according to fractionation and the recrystallization method of embodiment 2, obtain 393.5 gram solids after the oven dry, yield 62.7%.
The HPLC measurement result: (R)-3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; 8; 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone D-(+)-the dibenzoyl tartaric acid salts contg is 99.92%, enantiomorph (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; the content of the D-(+) of 8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt is 0.08%.
With 393.5 (the R)-3-methyl isophthalic acid that restrains-(pyrazole-3-yl)-6; 7; 8; the D-(+) of 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt joins in the water of 1.35L, at room temperature to the aqueous sodium hydroxide solution that wherein adds 40%; after regulating about pH to 6; to wherein adding sodium bicarbonate solid, behind the accent pH to 8, suction filtration goes out solid again.Solid is with dilute aqueous solution of sodium bicarbonate washing 2 times, wash 2 times with water after, obtain 159.8 gram white solids after the forced air drying, yield 58.9%.The HPLC measurement result: (R)-3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; 8; 9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone D-(+)-the dibenzoyl tartaric acid salts contg is 99.90%, enantiomorph (S)-3-methyl isophthalic acid-(pyrazole-3-yl)-6; 7; the content of the D-(+) of 8,9-tetrahydrochysene-3H-pyrazolo [3,4-c] isoquinoline 99.9-5(4H)-ketone-dibenzoyl tartaric acid salt is 0.10%.
Claims (11)
1. the method for splitting of formula 1 compound or its salt is characterized in that comprising the steps:
(1) split: racemic modification formula 1 compound or its salt and resolution reagent in-10 ℃～50 ℃ reaction generation diastereomer chirality hydrochlorates, are separated out from resolution solvent under temperature-10 ℃～50 ℃ in resolution solvent again;
(2) recrystallization: diastereomer chirality hydrochlorate places recrystallisation solvent to carry out the one or many recrystallization, until diastereomer chirality hydrochlorate is purified to more than 99.9%;
(3) neutralization: the formula 2 that step (2) is obtained or chirality hydrochlorate and the alkali of formula 3 carry out neutralization reaction, dissociate formula 2 or formula 3 compounds, and obtain formula 2 or formula 3 compounds by the mode of filtration or solvent extraction;
Wherein said resolution reagent is selected from D-(+)-dibenzoyl tartaric acid or its hydrate; L-(-)-dibenzoyl tartaric acid or its hydrate; the D-dextrocamphoric acid; the L-dextrocamphoric acid; D-Arg; L-arginine; D-tartrate; L-TARTARIC ACID; D-ASP; ASPARTIC ACID; left-handed o-Chloromelic acid; the dextrorotation o-Chloromelic acid; D-(+)-to methyldiphenyl formyl tartrate or its hydrate; L-(-)-to methyldiphenyl formyl tartrate or its hydrate; D-(+)-diacetylation tartrate or its hydrate; D-(-)-diacetylation tartrate or its hydrate; D-(+)-di-p-methoxy benzoyl tartrate or its hydrate; D-(+)-di-p-methoxy benzoyl tartrate or its hydrate.
2. method according to claim 1, the salt that it is characterized in that described racemic modification formula 1 compound is hydrochloride, hydrobromate, carbonate, vitriol, benzene sulfonate, acetate or formate.
3. method according to claim 1 is characterized in that described resolution reagent is selected from D-(+)-dibenzoyl tartaric acid or its hydrate, L-(-)-dibenzoyl tartaric acid or its hydrate.
4. method according to claim 1 is characterized in that described resolution reagent and the molar weight ratio of racemic modification formula 1 compound are 0.1～30:1, is preferably 1.05～2:1.
5. method according to claim 1, it is characterized in that described resolution solvent or recrystallisation solvent are selected from water, methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, 1,2-ethylene dichloride, 1, one or more mixed solvents in 1-ethylene dichloride, chloroform, ethyl acetate, ether, benzene, toluene, tetrahydrofuran (THF), the morpholine; Described resolution solvent preferably makes water, methylene dichloride and methanol mixed solvent; Described recrystallisation solvent preferably makes two or three mixed solvent in water, methylene dichloride and the methyl alcohol; The consumption of described resolution solvent and recrystallization solvent is V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=0～200:0～200:0～200:1, the preferred solvent amount is V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=1～40:1～40:1～40:1; In recrystallization process, methylene dichloride uses with other recrystallisation solvents or adds in Crystallization Process and uses.
6. method according to claim 1 is characterized in that in the step (1), and the temperature of reaction of racemic modification formula 1 compound or its salt and resolution reagent is-10 ℃～50 ℃, further is 5 ℃～30 ℃; The temperature of separating out diastereomer chirality hydrochlorate from resolution solvent is-10～50 ℃, further is 10～15 ℃; Stirring or leaving standstill the time of separating out is 0.5h～72h, preferred 10～15 hours.
7. method according to claim 1, it is characterized in that the re-crystallization step in the step (2) is: after diastereomer chirality hydrochlorate places recrystallisation solvent, at-10 ℃～100 ℃ lower 0.1-20h that stir, then at-10 ℃～50 ℃ lower crystallization 0.5-72h, filter.
8. method according to claim 7 is characterized in that in the step (2), and being stirred under-10 ℃～100 ℃ before the crystallization carried out, and preferably carries out under 50 ℃～80 ℃; Churning time before the crystallization is 0.5～2h; Tc is 0 ℃～40 ℃, preferred 0 ℃-5 ℃; Crystallization time is 10～15h.
9. according to claim 5 or 7 described methods, the consumption that it is characterized in that each solvent in the step (2) is V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=0～200:0～200:0～200:1 is preferably V
Methyl alcohol/ mL:V
Methylene dichloride/ mL:V
Water/ mL:M
Racemic modification/ g=1～40:1～40:1～40:1.
10. method according to claim 1 is characterized in that described alkali is selected from metal hydroxides, metal carbonic acid thing or metal bicarbonate thing, is preferably selected from sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus; Neutralization reaction to the pH value of reaction solution to 7-14, be preferably the pH value to 7-8.
11. the method for splitting of formula 1 compound or its salt is characterized in that comprising the steps:
(1) racemic modification formula 1 compound or its salt and resolution reagent generate diastereomer chirality hydrochlorates in-10 ℃～50 ℃ reactions in resolution solvent, separate out from resolution solvent under temperature-10 ℃～50 ℃ again;
(2) separate out in the step (1) fractionation mother liquor behind the diastereomer chirality hydrochlorate concentrated after, with alkali neutralization resolution reagent wherein, use again with step (1) in method in the resolution reagent repeating step (1) of opposite configuration separate out diastereomer chirality hydrochlorate;
(3) the diastereomer chirality hydrochlorate that step (2) is obtained places recrystallisation solvent to carry out the one or many recrystallization, until diastereomer chirality hydrochlorate is purified to more than 99.9%;
(4) formula 2 that step (3) is obtained or chirality hydrochlorate and the alkali of formula 3 carry out neutralization reaction, and is free and filter out formula 2 or formula 3 compounds;
Wherein said resolution reagent is selected from D-(+)-dibenzoyl tartaric acid or its hydrate; L-(-)-dibenzoyl tartaric acid or its hydrate; the D-dextrocamphoric acid; the L-dextrocamphoric acid; D-Arg; L-arginine; D-tartrate; L-TARTARIC ACID; D-ASP; ASPARTIC ACID; left-handed o-Chloromelic acid; the dextrorotation o-Chloromelic acid; D-(+)-to methyldiphenyl formyl tartrate or its hydrate; L-(-)-to methyldiphenyl formyl tartrate or its hydrate; D-(+)-diacetylation tartrate or its hydrate; D-(-)-diacetylation tartrate or its hydrate; D-(+)-di-p-methoxy benzoyl tartrate or its hydrate; D-(+)-di-p-methoxy benzoyl tartrate or its hydrate.
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| CN108239091B (en) * | 2016-12-26 | 2021-08-13 | 中国医学科学院药物研究所 | Resolution of 1-cyclohexyl-2- (5H-imidazo [5,1-a ] isoindol) ethyl-1-one |
| WO2020238528A1 (en) * | 2019-05-31 | 2020-12-03 | 江苏天士力帝益药业有限公司 | Intermediate tsl-1502m of parp inhibitor and preparation method thereof |
| WO2022021785A1 (en) * | 2020-07-30 | 2022-02-03 | 江苏天士力帝益药业有限公司 | Pharmaceutical composition containing tsl-1502m and use thereof |
| CN115819171A (en) * | 2022-07-25 | 2023-03-21 | 成都苑东生物制药股份有限公司 | Chiral resolution method of key intermediate in MOR receptor agonist synthetic route |
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